The aim of Virginia Commonwealth University's (VCU) competitive renewal application for a SCCPRIR is to continue the critical infrastructure, collaborations and synergy for clinical and translational research on the causes and treatment of infertility in the polycystic ovary syndrome (PCOS), which is the most common cause of anovulatory infertility in the U.S. The SCCPRIR is housed at VCU (Drs. John Nestler and Jerome Strauss) and the consortium is at Pennsylvania State University (Penn State; Dr. Richard Legro). The three Key Projects and the Pilot Project all focus on the contributions of insulin resistance and heredity to infertility in PCOS. Project I (Dr. Legro) will assess if genetic marker D19S884 identifies young girls at increased risk to develop PCOS, and the utility of this marker in identifying girls with premature pubarche who would respond to metformin to prevent progression to PCOS. Project II (Dr. Nestler) proposes a pharmacogenetic study to assess the impact of genotype variation of SNP_rs8111669 in gene STK11, or SNPs in other candidate genes identified by Project III, on ovulatory response to metformin. Correlating in vitro studies will determine the influence of SNP_rs9111699 genotype on metformin response in cultured human theca cells and hepatocytes. Continuing human genetic studies that have been pivotal in identifying a PCOS susceptibility gene (D19S884), Project III will find the determinants and identify the effects of this genetic marker. It will also investigate candidate genes for PCOS other than D19S884, and will extend the genetic analysis from PCOS (a qualitative trait) to PCOS-associated quantitative traits. The SCCPRIR will be supported by a strong Administrative Core that will coordinate research activities and provide centralized processing of samples, assays, recruitment, advertising, and other functions necessary for the successful operation of the SCCPRIR. This application for renewal of the SCCPRIR is particularly well timed given VCU's recent recruitment of a new Dean of the School of Medicine (Dr. Strauss) with new resources for support of research; commitment to research (in particular in Women's Health), establishment of a CTSA, and the NIH Roadmap; and demonstrated success in increasing NIH funding.